Continuous intravenous epoprostenol for chronic thromboembolic pulmonary hypertension.

Pathophysiological findings in chronic thromboembolic pulmonary hypertension (CTEPH) have suggested that a secondary small vessel arteriopathy may contribute to the haemodynamic impairment observed in these patients. It was hypothesised that this element of the elevated vascular resistance may be responsive to continuous intravenous epoprostenol therapy. Retrospectively, the clinical and haemodynamic responses to continuous intravenous epoprostenol were evaluated in nine CTEPH patients who subsequently underwent pulmonary thromboendarterectomy (PTE). Cardiopulmonary haemodynamics were determined prior to the initiation of epoprostenol, while on epoprostenol, prior to PTE, and after PTE. Six patients, treated for 2-26 months prior to PTE, experienced either clinical stability or improvement that was associated with a mean reduction in pulmonary vascular resistance (PVR) of 28% (median 33%, range 0-46%). Three patients, treated for 3-9 months, experienced clinical deterioration during epoprostenol administration, with a significant increase in PVR in two patients. Subsequent PTE resulted in a highly significant improvement of cardiac index, mean pulmonary artery pressure and total pulmonary resistance. To conclude, selected patients with chronic thromboembolic pulmonary hypertension may benefit clinically and haemodynamically from continuous intravenous epoprostenol treatment prior to pulmonary thromboendarterectomy. Factors predictive of a beneficial response, and whether this intervention influences either morbidity or mortality associated with pulmonary thromboendarterectomy, remain to be established.

Parathyroid hormone-related protein and lung injury after pulmonary thromboendarterectomy.

Parathyroid hormone-related protein (PTHrP) is an autocrine growth and differentiation factor for alveolar type II epithelial cells. Type II cells secrete pulmonary surfactant and are pluripotent cells with a role in alveolar epithelial repair after lung injury. The goals of this study were to investigate whether the levels of PTHrP in bronchoalveolar lavage liquid (BAL) varied between patients who did and did not develop lung injury after pulmonary thromboendarterectomy (PTE). BAL was performed in 48 patients undergoing PTE for unresolved pulmonary emboli. Samples were obtained following induction of anesthesia, following separation from cardiopulmonary bypass, and 48 h postoperatively. PTHrP was measured by radioimmunoassay. Lung injury was diagnosed in 23 patients on the basis of hypoxemia (PaO(2)/FIO(2) < 300) and the presence of lung infiltrates in the absence of infection or atelectasis. Patients with lung injury had significantly lower preoperative BAL levels of PTHrP, 21 (21-30) pg/ml (median, interquartile gap), compared to patients without lung injury, 34 (21-41) pg/ml (P < 0.05). Preoperative BAL PTHrP levels < 32 pg/ml predicted lung injury with a positive predictive value of 60% and negative predictive value of 82%. The odds of developing lung injury for patients with preoperative PTHrP levels below this cutpoint were 6 times the odds for patients with higher levels.

Chronic thromboembolic pulmonary hypertension.

Remarkable advances have occurred over the past 2 decades in the diagnostic approach, surgical management, and postoperative care of patients afflicted with chronic thromboembolic pulmonary hypertension. Despite these advances, a great deal needs to be achieved if the morbidity and mortality of the disease process are to be reduced further. First, the preliminary insights that have been achieved into the natural history of the disease must be defined further. The level of pulmonary hypertension encountered in most patients with chronic thromboembolic pulmonary hypertension at the time of initial clinical recognition cannot be reached on an acute basis. Gradual hemodynamic progression, therefore, must occur over time. The basis for this progression, why it occurs in certain patients and not others, following an acute thromboembolic event and why it seems to occur over months in certain patients and over decades in others, remain entirely speculative. It is possible that the overall extent of central pulmonary vascular obstruction represents the primary pathophysiologic determinant of disease progression. Given the lack of correlation between the degree of central thromboembolic obstruction and hemodynamic impairment in certain patients, however, it is also possible that other factors, such as the circulating vasoconstrictors, the development of a hypertensive pulmonary arteriopathy, an individual genetic predisposition to pulmonary hypertension, or the compensatory adaptations of the right ventricle, contribute to the extent and rate of disease progression. By identifying and sequentially evaluating patients with persistent pulmonary vascular obstruction or pulmonary hypertension following an acute thromboembolic event, valuable insights into the natural history of thromboembolic pulmonary hypertension and other variants of pulmonary hypertension might be achieved. It is also important to recognize that the development of chronic thromboembolic pulmonary hypertension represents a failure in the long-term management or follow-up surveillance of those with documented acute thromboembolic disease. Recent insights into the recurrent nature of acute thromboembolic disease and its potential for only partial resolution in a number of afflicted individuals suggest that a repeat perfusion scan and, if abnormal, an echocardiogram be performed at the time of anticipated discontinuation of anticoagulation in patients with documented pulmonary embolic disease. Although the cost-effectiveness of this approach has been questioned in the past, recent data suggest that doing so would help identify that subset of patients with unresolved embolism, provide additional information regarding the optimal duration of anticoagulation, and provide a new baseline study for patients in whom anticoagulation is discontinued and who subsequently present with suspected embolic recurrence. Improved diagnostic techniques are also necessary if the mortal risk of thromboendarterectomy is to be reduced. Even in the setting of a broad experiential base, prognostic uncertainty exists in approximately 10% of patients before operative intervention. Because many of these patients will benefit from the procedure, and because many are ineligible for transplantation for reason of age or other restriction, it has been the authors' practice to offer surgery to these patients, although at an assumed higher risk. To not do so would be to deny a potentially lifesaving procedure to many who would benefit and who might be left without an effective therapeutic alternative. The ability to better define the group of patients who will not benefit from surgery, however, would spare those patients the morbid and mortal risks of the procedure and provide a basis for the investigation of other therapeutic alternatives such as pulmonary vasodilating agents. Finally, this patient population offers a unique opportunity to enhance understanding of the pathophysiologic mechanisms involved in acute lung injury. The population involved is uniform, the predisposing event is consistent, the time of onset is predictable, and, compared with other populations at risk for acute lung injury, the presence of confounding variables is negligible. It also provides a unique opportunity to evaluate pharmacologic interventions designed to prevent or diminish the occurrence of acute lung injury and postoperative management strategies designed to minimize its impact.

Pulmonary thromboendarterectomy combined with other cardiac operations: indications, surgical approach, and outcome.

BACKGROUND: Patients with pulmonary hypertension due to chronic thromboembolic disease benefit from pulmonary thromboendarterectomy. A subset of these patients present with concomitant coronary or valvular disease. METHODS: From July 1990 to July 2000, 90 patients (68 males, 22 females, mean age 68 years) with pulmonary vascular resistance (PVR) ranging from 297 to 2261 dynes x sec x cm(-5) underwent pulmonary thromboendarterectomy in conjunction with coronary bypass grafting (59 patients), coronary artery bypass grafting/foramen ovale closure (24 patients), tricuspid annuloplasty (3 patients), mitral valve repair (2 patients), and aortic valve replacement (2 patients). The perioperative and hemodynamic outcomes of these patients were compared with the cohort of 1,100 isolated pulmonary thromboendarterectomies performed at our institution during this time. RESULTS: Overall perioperative survival (93.3%; 84 of 90 patients) and mean diminution in PVR (521 dynes x sec x cm(-5)) for patients undergoing combined operations were similar to those undergoing pulmonary thromboendarterectomy alone (94.2% survival; 1034 of 1100 patients; 547 dynes x sec x cm(-5) mean PVR reduction). Although patients undergoing combined operations were older (mean age 68 vs 50 years, p < 0.0001), had longer hospital stays (median 14 vs 9 days), and had worse left ventricular function (mean preoperative cardiac output 3.1 vs 4.4, p < 0.0001), there was no difference in cross-clamp time, resolution of tricuspid regurgitation, or postoperative systolic function between these two groups. CONCLUSIONS: Pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension may be performed safely in conjunction with other cardiac operations. Older patients evaluated for pulmonary thromboendarterectomy should be screened for concomitant coronary and valvular disease.

Fatal paradoxic embolism occurring during IVC filter insertion in a patient with chronic pulmonary thromboembolic disease.

A patient diagnosed with chronic thromboembolic disease experienced a fatal intraprocedural paradoxic embolism during inferior vena cava (IVC) filter insertion. The frequency of patent intra-atrial shunts in patients with chronic thromboembolic disease is surprisingly high, occurring in approximately 29.5% of patients with chronic thromboembolic disease. Prevention of embolic events during venous interventions in such cases requires that the operator recognize that central shunts may be present and strictly adhere to meticulous technique during IVC filter insertion.

"High probability" perfusion lung scans in pulmonary venoocclusive disease.

"High-probability" ventilation/perfusion (V/Q) lung scans generally indicate proximal pulmonary arterial occlusion by thromboemboli or, rarely, other processes such as tumors, fibrosing mediastinitis, or vasculitis. In this report we describe three patients with high probability V/Q scans in whom pulmonary angiography failed to demonstrate arterial occlusion. All three patients were determined to have pulmonary venoocclusive disease (PVOD). In two patients, a tissue diagnosis of PVOD was made, in one case with explanted tissue taken after a successful heart-lung transplant and in the other case with tissue taken at autopsy. PVOD in the third patient was diagnosed with pulmonary venography. A potential explanation for the discrepancy between perfusion lung scan and pulmonary angiographic findings in PVOD is discussed.

The use of cylexin (CY-1503) in prevention of reperfusion lung injury in patients undergoing pulmonary thromboendarterectomy.

Pulmonary thromboendartectomy (PTE) for chronic thromboembolic pulmonary hypertension may be complicated by reperfusion lung injury. This has previously been demonstrated to be neutrophil-mediated. We postulated that blocking selectin-mediated adhesion of neutrophils to the endothelium with Cylexin (CY-1503) would prevent reperfusion lung injury in this patient population. In this double-blind, randomized, placebo-controlled, parallel study, 26 patients received Cylexin the day of surgery and 25 received placebo. Significantly fewer patients in the treated group (31%) compared with the placebo group (60%) developed lung injury (p = 0.036). However, the average number of days of mechanical ventilation, days in the intensive care unit (ICU) and hospital, as well as mortality were not significantly different between the treatment groups. Those with reperfusion lung injury had significantly elevated percent neutrophils, total protein, and soluble P-selectin in bronchoalveolar lavage fluid compared with those without lung injury. We conclude that reperfusion lung injury after PTE is a high-permeability lung injury and its incidence can be reduced by the administration of Cylexin on the day of surgery.

Successful pulmonary thromboendarterectomy in a patient with Klippel-Trenaunay syndrome.

Klippel-Trenaunay syndrome (KTS) is a congenital disorder characterized by a triad of cutaneous vascular nevi, soft tissue or bony hypertrophy, and varicose veins or venous malformations involving one or more extremities. An incidence of venous thromboembolism of up to 22% has been reported in this disorder. Also reported is the development of chronic thromboembolic pulmonary hypertension (CTEPH) and subsequent death from right ventricular failure. We report the first patient with KTS to undergo a successful pulmonary thromboendarterectomy for CTEPH.

Chronic thromboembolic pulmonary hypertension.

Under most circumstances, chronic thromboembolic pulmonary hypertension represents a correctable form of pulmonary hypertension. Approximately 1500 thromboendarterectomy procedures have now been performed worldwide. Mortality rates reported by established programs with experience in the management of patients with this disease process have fallen to a range of 6 to 8%. This reduction in mortality has been contributed to by several factors: improved methods of preoperative evaluation and more selective surgical referral, increased surgical experience and refined techniques, and an increased understanding of the unique postoperative problems that occur following pulmonary thromboendarterectomy. Despite these advances, a great deal more needs to be accomplished. The early natural history and pathophysiologic mechanisms of the disease remain uncertain; improved diagnostic techniques are required; and the most feared complication of the procedure, reperfusion pulmonary edema, remains enigmatic in terms of its pathogenesis, prevention, and therapy.

Reoperative pulmonary thromboendarterectomy.

BACKGROUND: Recurrent symptomatic pulmonary hypertension is uncommon after primary pulmonary thromboendarterectomy (PTE). We reviewed our experience with patients undergoing repeat PTE to determine the risk factors for recurrent disease, and the selection criteria, relative risks, and functional outcomes of reoperative PTE. METHODS: Since 1990, 13 of 870 (1.5%) patients underwent reoperative PTE at our institution. These 7 men and 6 women (mean age 38.6 years) were contrasted with the most recent 225 patients (111 men, 114 women, mean age 52.7 years) who underwent primary PTE for whom complete hemodynamic data are available. The preoperative evaluation of all patients was similar. Pulmonary hemodynamic data and outcome measures were compared between groups. RESULTS: Of 13 reoperated patients: 69% (9/13) had their primary operation at another institution, 54% (7/13) initially underwent unilateral PTE, 38% (5/13) had identifiable coagulation disorders, 38% (5/13) had ineffective caval filtration, 31% (4/13) had suboptimal anticoagulation management, and 31% (4/13) had complete unilateral pulmonary artery obstruction. The mean interval to reoperation was 5.2 years (range 0.7 to 10.9 years). All control patients underwent bilateral PTE using hypothermic circulatory arrest. Operative mortality was 7.7% (1/13) with reoperation vs 8.4% (19/225) in controls. No difference (p = NS) was observed between groups in the preoperative pulmonary artery pressure (PAP) or pulmonary vascular resistance; however, the control group had a significantly (p < 0.05) greater reduction in the postoperative PAP (46/19, mean 28 mm Hg vs 59/23, mean 35 mm Hg) and PVR (271 +/- 172 vs 399 +/- 154 dynes/s/cm(-5)) compared with the redo group. No substantial difference in morbidity or functional outcomes was observed between groups. CONCLUSIONS: Reoperative PTE can be performed with a perioperative risk comparable with primary PTE, although the improvement in pulmonary hemodynamics is not as favorable. Bilateral primary operation, effective caval filtration, and vigilant anticoagulant management would prevent the need for most reoperative PTEs.

Atrial septostomy as a bridge to lung transplantation in patients with severe pulmonary hypertension.

Long waiting times for lung transplantation have limited the survival of patients with advanced pulmonary hypertension. Atrial septostomy has been used in this group of patients in an attempt to prolong survival. We evaluated the results of atrial septostomy in 12 patients using the static graded balloon dilation technique. Between December 1990 and May 1998, 10 women and 2 men (ages 13 to 56 years, mean 37 years) underwent atrial septostomy. Nine patients had primary and 3 patents had secondary pulmonary hypertension. Five patients deteriorated despite long-term intravenous prostacyclin infusions. The atrial septum was crossed with a Brockenbrough needle, followed by an 0.035-J exchange wire and progressively larger catheter balloons for atrial septal dilation, until systemic oxygen saturation decreased 5% to 10%. An atrial septal defect was successfully created in each patient. The mean right atrial pressure decreased from 23 to 18 mm Hg and the mean systemic oxygen saturation decreased from 93% to 85%. The mean cardiac index increased from 1.7 to 2.1 L/min/m2 and the mean systemic oxygen transport increased from 268 to 317 ml/min/m2. Complications occurred in 3 patients: transient hypotension during transesophageal echocardiography, a femoral pseudoaneurysm, and a femoral arteriovenous fistula. After septostomy, 6 patients had clinical improvement (resolution of ascites, edema, and no further episodes of syncope); 5 of these 6 patients underwent lung transplantation a mean of 6.1 months after septostomy. Six patients did not have clinical improvement after septostomy. Atrial septostomy improves the hemodynamic status and may be useful as a bridge to lung transplantation in selected patients with pulmonary hypertension.

Long-term outcome after pulmonary thromboendarterectomy.

This study evaluated long-term outcome of pulmonary thromboendarterectomy (PTE) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Survival, functional status, quality of life, health care utilization, and relationships between these parameters and postoperative pulmonary hemodynamics were assessed. Questionnaires were mailed to 420 patients who were more than 1 yr post-PTE; 308 responded (mean age, 56 yr [range, 19-89 yr]; mean years since PTE, 3.3 [range, 1- 16]). Survival after PTE was 75% at > 6 yr. After surgery, symptoms were markedly reduced. Median distance walked was 5,280 ft; 56 patients could walk "indefinitely." Of the working population, 62% of patients unemployed before PTE returned to work. Post-PTE patients scored several quality of life components of the Rand SF-36 slightly lower than reported normals but significantly higher than did pre-PTE patients. Ten percent of patients used oxygen. Ninety-three percent were in NYHA Class I or II. Disease-related hospitalizations/ER visits were minimal. A relationship was shown between 48 h postoperative pulmonary vascular resistance (PVR) and walking and stair-climbing ability, NYHA class, dyspnea scores, and the physical function and general health quality of life components. These data indicate that PTE offers most CTEPH patients substantial improvement in survival, function, and quality of life, with minimal disease-related health care utilization.

Historical perspective: surgery for chronic thromboembolic disease.

Obstruction of major pulmonary vessels with organized thromboemboli is a rare sequelae of acute pulmonary embolic disease. Depending on the extent and duration of vascular occlusion, patients experiencing this unusual disorder may develop significant pulmonary hypertension and cor pulmonale. If left untreated, the ultimate clinical outcome is right heart failure and death. Over the past several decades, the description of this clinical entity has evolved from an autopsy curiosity to a recognized cause of chronic pulmonary hypertension. Also, during this same time period, surgical capabilities have greatly advanced, providing these patients a potentially life-saving remedy for this debilitating form of pulmonary vascular disease. This article provides a historical perspective for our current understanding of major vessel chronic thromboembolic pulmonary hypertension as a distinct clinical disorder. It also chronicles the developments in surgical techniques that have made thromboendarterectomy of the pulmonary arterial bed a reality.

Outcome after pulmonary thromboendarterectomy.

Pulmonary thromboendarterectomy (PTE) surgery is an effective treatment for the majority of patients with chronic thromboembolic pulmonary hypertension (CTEPH), with an acceptable mortality rate. The immediate outcome after PTE has repeatedly shown a dramatic decline in pulmonary vascular resistance, echocardiographic evidence of reduced right heart pressure, and increased perfusion on lung scan. Prospective long-term follow-up studies (1 to 4 years post-PTE) have found most patients to be in New York Heart Association class I or II, with significantly improved quality of life and ability to walk, climb stairs, return to work, and perform household tasks. Disease-related symptoms and hospitalizations and/or emergency room visits have also been significantly reduced. These findings indicate an improved functional status and longer life expectancy can be achieved after PTE.

Postoperative management of the patient undergoing pulmonary thromboendarterectomy.

The postoperative course of the patient undergoing pulmonary thromboendarterectomy poses a unique series of challenges in terms of ventilatory care and hemodynamic management. Experience, cooperation, and interaction are necessary among the various disciplines providing care for these patients during the preoperative, operative, and postoperative phases of care. The purpose of this article is to share the approach necessary for the optimal postoperative care of the patient undergoing thromboendarterectomy, to present the theoretical justification for this care, and to delineate the areas of uncertainty that still exist.

Evaluation of patients with suspected chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) can be a difficult diagnosis to establish, typically requiring a high index of suspicion on the part of the clinician when challenged by a patient reporting exertional dyspnea. The importance of this diagnosis is heightened by the appreciation that it is a potentially curable form of pulmonary hypertension, by a surgical procedure called pulmonary thromboendarterectomy. This article highlights the clinical presentation, evaluation, and criteria for surgical candidacy of those patients suspected of having CTEPH.

Successful pulmonary thromboendarterectomy in two patients with sickle cell disease.

Patients with sickle cell disease have been reported to have an increased risk of thromboembolism and pulmonary hypertension. Some of these patients may benefit from pulmonary thromboendarterectomy (PTE), a procedure that requires profound hypothermia, cardiopulmonary bypass, and periods of circulatory arrest, factors that may potentially increase the risk of sickling. Two patients with sickle cell disease (sickle-thalassemia [Hb S/beta+] and Hb SS) presented to the Pulmonary Vascular Center of UCSD Medical Center with significant shortness of breath and limitation of daily activities. Both of these patients were found to have surgically accessible chronic thromboembolic disease with pulmonary hypertension. PTE was performed in both patients using exchange transfusion, with avoidance of anemia, hypoxia, and acidosis. A successful outcome with resolution of pulmonary hypertension was achieved in both cases. To our knowledge this is the first report of patients with sickle cell disease who successfully underwent PTE for chronic thromboembolic pulmonary hypertension.